Abstract
Prader–Willi syndrome (PWS) is a complex genetic disorder that, besides cognitive impairments, is characterized by hyperphagia, obesity, hypogonadism, and growth impairment. Proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency, a rare recessive congenital disorder, partially overlaps phenotypically with PWS, but both genetic disorders show clear dissimilarities as well. The recent observation that PCSK1 is downregulated in a model of human PWS suggests that overlapping pathways are affected. In this review we will not only discuss the mechanisms by which PWS and PCSK1 deficiency could lead to hyperphagia but also the therapeutic interventions to treat obesity in both genetic disorders.
Highlights
Prader–Willi syndrome (PWS) is a complex genetic disorder that, besides cognitive impairments, is characterized by hyperphagia, obesity, hypogonadism, and growth impairment
Prader–Willi syndrome (PWS) is a multisystemic complex genetic disorder resulting from the absence of expression of the paternally inherited genes on chromosome 15q11.2-q13 [10]
Besides the arcuate nucleus (ARC), PC1/3 is present in several other hypothalamic regions including the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), and the lateral hypothalamus (LH), where it could be processing other neuropeptides involved in feeding behavior including brain-derived neurotrophic factor (BDNF), corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), orexins, and melanin-concentrating hormone (MCH)
Summary
Obesity, defined as a disproportionate body weight for height with an excessive accumulation of adipose tissue [1], is the result of a net imbalance of caloric intake over energy expenditure over time [2], caused by several genetic and nongenetic risk factors [3]. Syndromic obesity can be defined as the presence of obesity along with additional characteristics, including intellectual disability, dysmorphic features, and congenital abnormalities affecting specific organ systems [6]. Prader–Willi syndrome (PWS) is a multisystemic complex genetic disorder resulting from the absence of expression of the paternally inherited genes on chromosome 15q11.2-q13 (alleles from the maternally contributed chromosome are normally inactivated by epigenetic factors and not expressed) [10]. This lack of expression is due, in 65–75% of cases, to paternal deletion [10]. Other endocrine issues such as central adrenal insufficiency, hypothyroidism, impaired glucose tolerance, and diabetes mellitus can be found in PWS in addition to other findings including sleep abnormalities, strabismus, hip dysplasia, scoliosis, recurrent respiratory infections, and others (bone fractures caused by osteopenia, leg edema and ulceration, skin picking, altered temperature sensation, decreased saliva flow, high vomiting threshold, or seizures) [10]
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